It is well established that HTLV-I is the etiologic agent for a number of diseases, including adult T-cell leukemia and a neurological disorder called HAM/TSP. In addition, accumulating evidence suggests that HTLV-II may be involved in disease, as well. These disease correlations and the fact that HTLV-I and HTLV-II can be transmitted by transfusion have led to the recommendation that blood donors be screened for evidence of HTLV-I and HTLV-II infection. however, the connection between the virus and disease is not known. The purpose of this project is to examine molecular mechanisms which could explain such a connection, thereby establishing a basis for HTLV-associated transfusion-transmitted disease. In addition, this project seeks to determine if current methods for screening blood donors are sufficient to detect both HTLV-I and HTLV-II infections. In the area of HTLV-I Tax protein on gene expression in NT2-N, post-mitotic cells that are remarkably similar to primary human neurons. Treatment of NT2-N with soluble Tax resulted in the synthesis of TNF-alpha in a dose- dependent manner. Tax-induced TNF-alpha expression was relatively rapid, peaking within 6 hours of treatment. Remarkably, exposing NT2-N to Tax for as little as 5 minutes was sufficient to result in TNF-alpha production, indicating that the induction of TNF-alpha in MT2-N does not require Tax to be continually present. Given the toxicity of TNF-alpha for oligodendrocytes, the myelin-producing cells of the central nervous system, these results suggest that extracellular Tax may play a role in the demyelination observed in HAM/TSP through the induction of TNF-alpha in neurons. In addition, samples of cerebrospinal fluid and blood from HTLV-I-infected individuals with and without disease are being examined for the presence of Tax protein in an effort to correlate the presence of Tax with disease. In the area of detection, it was determined that some of the currently licensed donor screening tests for antibodies to HTLV-I are able to detect antibodies to HTLV-II, based on cross-reactivity on HTLV-II antibodies for HTLV-I antigens. In this study, which examined the ability of screening tests containing HTLV-I antigens alone or in combination with HTLV-II antigens to detect antibodies to HTLV-II in a panel of anti-HTLV- II positive specimens, it was determined that HTLV-I antigen only tests were sensitive for antibodies to HTLV-II. Additional samples are being tested to determine whether the presence of HTLV-II antigens in a screening test confers any additional sensitivity for antibodies to HTLV- II.